US20210346321A1 - Pharmaceutical composition containing alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate, tartrate or combination thereof, and preparation method therefor - Google Patents
Pharmaceutical composition containing alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate, tartrate or combination thereof, and preparation method therefor Download PDFInfo
- Publication number
- US20210346321A1 US20210346321A1 US17/283,627 US201917283627A US2021346321A1 US 20210346321 A1 US20210346321 A1 US 20210346321A1 US 201917283627 A US201917283627 A US 201917283627A US 2021346321 A1 US2021346321 A1 US 2021346321A1
- Authority
- US
- United States
- Prior art keywords
- methyl
- naphthalen
- yloxy
- octenediamide
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 title claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 title abstract description 7
- 229910019142 PO4 Inorganic materials 0.000 title abstract description 3
- 239000010452 phosphate Substances 0.000 title abstract description 3
- 229940095064 tartrate Drugs 0.000 title description 7
- 238000002360 preparation method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 239000000843 powder Substances 0.000 claims abstract description 22
- 239000003826 tablet Substances 0.000 claims abstract description 22
- 239000002775 capsule Substances 0.000 claims abstract description 20
- 238000002347 injection Methods 0.000 claims abstract description 14
- 239000007924 injection Substances 0.000 claims abstract description 14
- 239000008187 granular material Substances 0.000 claims abstract description 10
- 239000006188 syrup Substances 0.000 claims abstract description 7
- 235000020357 syrup Nutrition 0.000 claims abstract description 7
- -1 cyclohexanyl Chemical group 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 230000001954 sterilising effect Effects 0.000 claims description 14
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 12
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 238000004659 sterilization and disinfection Methods 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 4
- 125000006636 (C3-C8) cycloalkylcarbonyl group Chemical group 0.000 claims description 4
- AUGCSOFQTDKPSO-RGVLZGJSSA-N (e)-n-[3-(dimethylamino)propyl]-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1=CC=C2C(OC/C(C(=O)NCCCN(C)C)=C\CCCCC(=O)NO)=CC=CC2=C1 AUGCSOFQTDKPSO-RGVLZGJSSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000011247 coating layer Substances 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 4
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 claims description 4
- 150000003053 piperidines Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
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- PATWZPCFBNJJCK-LSHDLFTRSA-N (e)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)-n-(1-propan-2-ylpiperidin-4-yl)oct-2-enediamide Chemical compound C1CN(C(C)C)CCC1NC(=O)C(=C\CCCCC(=O)NO)\COC1=CC=CC2=CC=CC=C12 PATWZPCFBNJJCK-LSHDLFTRSA-N 0.000 claims description 2
- LERXQMLCFARRIC-UFFVCSGVSA-N (e)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)-n-(1-propan-2-ylpyrrolidin-3-yl)oct-2-enediamide Chemical compound C1N(C(C)C)CCC1NC(=O)C(=C\CCCCC(=O)NO)\COC1=CC=CC2=CC=CC=C12 LERXQMLCFARRIC-UFFVCSGVSA-N 0.000 claims description 2
- HDUMAEHTJLXNPY-DJKKODMXSA-N (e)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)-n-(thiophen-2-ylmethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NCC1=CC=CS1 HDUMAEHTJLXNPY-DJKKODMXSA-N 0.000 claims description 2
- JFVDRPFRDGMNPX-UFFVCSGVSA-N (e)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)-n-[3-(2-oxopyrrolidin-1-yl)propyl]oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NCCCN1CCCC1=O JFVDRPFRDGMNPX-UFFVCSGVSA-N 0.000 claims description 2
- VLERWGIRJCSZBV-ODCIPOBUSA-N (e)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)-n-[[4-(trifluoromethoxy)phenyl]methyl]oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NCC1=CC=C(OC(F)(F)F)C=C1 VLERWGIRJCSZBV-ODCIPOBUSA-N 0.000 claims description 2
- OXXIMKIBPBGDBZ-QGMBQPNBSA-N (e)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)-n-pyrrolidin-3-yloct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NC1CCNC1 OXXIMKIBPBGDBZ-QGMBQPNBSA-N 0.000 claims description 2
- KYNZFXFAZXHSCE-VXLYETTFSA-N (e)-n'-hydroxy-n-(1-methoxypropan-2-yl)-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1=CC=C2C(OC/C(C(=O)NC(C)COC)=C\CCCCC(=O)NO)=CC=CC2=C1 KYNZFXFAZXHSCE-VXLYETTFSA-N 0.000 claims description 2
- MJKWUXCIQUYXRT-GIJQJNRQSA-N (e)-n'-hydroxy-n-(2-methoxyethyl)-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1=CC=C2C(OC/C(C(=O)NCCOC)=C\CCCCC(=O)NO)=CC=CC2=C1 MJKWUXCIQUYXRT-GIJQJNRQSA-N 0.000 claims description 2
- SPFCWPYSSCVUAF-ZVBGSRNCSA-N (e)-n'-hydroxy-n-(3-imidazol-1-ylpropyl)-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NCCCN1C=CN=C1 SPFCWPYSSCVUAF-ZVBGSRNCSA-N 0.000 claims description 2
- AHJMBYSCBHQGEN-LSFURLLWSA-N (e)-n'-hydroxy-n-[(4-methoxyphenyl)methyl]-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1=CC(OC)=CC=C1CNC(=O)C(=C\CCCCC(=O)NO)\COC1=CC=CC2=CC=CC=C12 AHJMBYSCBHQGEN-LSFURLLWSA-N 0.000 claims description 2
- QXRDPEPXAINRIK-GZIVZEMBSA-N (e)-n'-hydroxy-n-[2-(4-hydroxyphenyl)ethyl]-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NCCC1=CC=C(O)C=C1 QXRDPEPXAINRIK-GZIVZEMBSA-N 0.000 claims description 2
- AWJUBYVLCUBBHW-NUGSKGIGSA-N (e)-n'-hydroxy-n-[2-(4-methoxyphenyl)ethyl]-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1=CC(OC)=CC=C1CCNC(=O)C(=C\CCCCC(=O)NO)\COC1=CC=CC2=CC=CC=C12 AWJUBYVLCUBBHW-NUGSKGIGSA-N 0.000 claims description 2
- XMFQQXGTUUFSCH-DHRITJCHSA-N (e)-n-(1-benzylpyrrolidin-3-yl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NC(C1)CCN1CC1=CC=CC=C1 XMFQQXGTUUFSCH-DHRITJCHSA-N 0.000 claims description 2
- QCQOWAULLDMUBM-BHGWPJFGSA-N (e)-n-(1-cyclohexylpyrrolidin-3-yl)-n'-hydroxy-2-(naphthalen-2-yloxymethyl)oct-2-enediamide Chemical compound C=1C=C2C=CC=CC2=CC=1OC\C(=C/CCCCC(=O)NO)C(=O)NC(C1)CCN1C1CCCCC1 QCQOWAULLDMUBM-BHGWPJFGSA-N 0.000 claims description 2
- DWUWNRYOCMZDCK-AUEPDCJTSA-N (e)-n-(1-cyclopentylpiperidin-4-yl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NC(CC1)CCN1C1CCCC1 DWUWNRYOCMZDCK-AUEPDCJTSA-N 0.000 claims description 2
- ZRMXVNQHSVWJKB-ODCIPOBUSA-N (e)-n-(1-cyclopropylpiperidin-4-yl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NC(CC1)CCN1C1CC1 ZRMXVNQHSVWJKB-ODCIPOBUSA-N 0.000 claims description 2
- PLCUEFKAXZAWRU-DNTJNYDQSA-N (e)-n-(1-cyclopropylpyrrolidin-3-yl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NC(C1)CCN1C1CC1 PLCUEFKAXZAWRU-DNTJNYDQSA-N 0.000 claims description 2
- FBMBRHBJRRMJMS-UFFVCSGVSA-N (e)-n-(1-ethylpiperidin-4-yl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1CN(CC)CCC1NC(=O)C(=C\CCCCC(=O)NO)\COC1=CC=CC2=CC=CC=C12 FBMBRHBJRRMJMS-UFFVCSGVSA-N 0.000 claims description 2
- CKTLNGMIRRQTRD-KEBDBYFISA-N (e)-n-(1-ethylpyrrolidin-3-yl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C1N(CC)CCC1NC(=O)C(=C\CCCCC(=O)NO)\COC1=CC=CC2=CC=CC=C12 CKTLNGMIRRQTRD-KEBDBYFISA-N 0.000 claims description 2
- RKVSGRANVSFJCY-DJKKODMXSA-N (e)-n-(furan-2-ylmethyl)-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NCC1=CC=CO1 RKVSGRANVSFJCY-DJKKODMXSA-N 0.000 claims description 2
- BTXIRHGRWJVJEZ-ZMOGYAJESA-N (e)-n-[1-(cyclohexanecarbonyl)pyrrolidin-3-yl]-n'-hydroxy-2-(naphthalen-1-yloxymethyl)oct-2-enediamide Chemical compound C=1C=CC2=CC=CC=C2C=1OC\C(=C/CCCCC(=O)NO)C(=O)NC(C1)CCN1C(=O)C1CCCCC1 BTXIRHGRWJVJEZ-ZMOGYAJESA-N 0.000 claims description 2
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Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate compound, an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound or a combination thereof.
- the present invention relates to a method for preparing the pharmaceutical composition.
- a histone is a basic protein that binds to DNA in the eukaryotic cell nucleus, and reversible histone acetylation occurs on the amino group of a specific lysine residue in each molecule of the histone.
- the histone acetylation reaction is related to the formation of high-order structure of chromatin or the cell-division cycle, so it is involved in the regulation of expression of gene information, and stably regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs).
- HATs histone acetyltransferases
- HDACs histone deacetylases
- HDAC has recently been found to play a role in promoting cell proliferation as it is highly expressed in poor environmental conditions such as hypoxia, low glucose and cell carcinogenesis to inhibit the expression of cell proliferation. Therefore, it is recognized as an important factor in regulating cell carcinogenesis and differentiation. That is, while high acetylation of chromatin inhibits cell proliferation and promotes differentiation, HDAC plays a crucial role in inducing cell proliferation through deacetylation of histones. This is supported by the results of inhibition of cell proliferation or angiogenesis by treatment with HDAC inhibitors. There is a need for the development of HDAC inhibitors having higher selectivity and excellent medicinal efficacy. Accordingly, the present inventors confirmed the possibility of alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide as an HDAC inhibitor, and thus have been conducting research on this.
- alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide has a property of absorbing moisture in the atmosphere, there may occur a problem that is vulnerable to physicochemical stability.
- a number of purification operations for removal of related substances generated by moisture absorption can increase the production cost, and high hygroscopicity makes difficult to maintain the solid state, causing difficulties in mass-producing solid preparations.
- the present invention provides a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection comprising an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide hydrochloride compound, an alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound or a combination thereof.
- the present invention provides a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection comprising a compound of formula 1 (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate), a compound of formula 2 (alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate) or a combination thereof.
- a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection comprising a compound of formula 1 (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate), a compound of formula 2 (alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate) or a combination thereof.
- R 1 is C 1-3 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halophenyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, cyclohexanyl, furanyl, thiophenyl, imidazole, imidazolidyl C 1-3 alkyl, C 1-3 alkylamino, di-C 1-3 alkylamino, hydroxyphenyl, tetrahydrofuranyl, cyclohexyl, cyclohexenyl, oxopyrrolidinyl, C 1-3 alkoxyphenyl, di-C 1-3 alkylaminophenyl, C 1-3 alkylpyrrolidinyl and trifluoromethoxyphenyl; pyrrolidine unsubstituted or substituted with C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-3 alkyl, benzyl, C
- the coating layer may be present in an amount of 1 to 10% by weight based on 100 parts by weight of the tablet or capsule.
- the composition may be a pharmaceutical composition for injection having a liquid or lyophilized form.
- a pharmaceutical composition for an anticancer agent comprising a compound of formula 1, a compound of formula 2 or a combination thereof.
- the present invention provides a method for preparing a pharmaceutical composition in the form of a tablet, granule, powder, capsule, dry syrup or injection, the method comprising:
- the method may further comprise additionally adding a solvent having a lower solubility than the organic solvent of step 1).
- the organic solvent of step 1) may comprise one or more selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile and ethyl acetate.
- the solvent having a lower solubility than the organic solvent of step 1) may comprise one or more selected from the group consisting of alcohols including methanol, ethanol and propanol, tetrahydrofuran, acetonitrile and acetone.
- the method may further comprise sterilizing by a high-temperature decompression sterilization method or aseptic filtration method.
- the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate compound, the alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound, or combinations thereof of the present invention it is possible to improve stability against moisture while maintaining properties such as medicinal efficacy and effective amount.
- by improving hygroscopicity production and commercialization processes of the preparations can be simplified.
- by maintaining stability during the manufacturing process to prevent the production of related substances it is possible to provide a compound and pharmaceutical composition having safety and easy of manufacture.
- FIG. 1 is a graph showing the dissolution pattern of tablets comprising alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate.
- FIG. 2 is a graph showing the dissolution pattern of capsules comprising alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate.
- FIG. 3 is a graph showing the results of measuring the amount of related substances produced in Example 12.
- FIG. 4 is a graph showing a change in moisture content.
- FIG. 5 is a graph comparing the amount of related substances produced in Examples and Comparative Examples.
- FIG. 6 is a graph showing the amount of related substances produced in Example 13 according to storage temperature.
- FIG. 7 is a graph showing the amount of related substances produced in Example 14 according to storage temperature.
- FIG. 8 is a photograph showing appearance of the composition for injection having a lyophilized form comprising alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate.
- composition refers to any composition which can be a relatively non-toxic to a subject to be administered and have harmless effective action.
- pharmaceutical composition may refer to any organic or inorganic compound formulation in that side effects resulting from the composition do not impair the efficacy of the drug, and that does not cause serious irritation to a subject to be administered by the compound and does not impair the biological activities and properties of the compound.
- subject to be administered may be used interchangeably with ‘subject to be applied’, ‘individual to be administered’ and ‘organism to be administered’, and may refer to any animals including humans in need of HDAC inhibition.
- the pharmaceutical composition comprising an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate compound, an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate compound or a combination thereof according to the embodiment of the present invention will be described in more detail.
- alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide or a derivative thereof as a histone deacetylase (HDAC) inhibitor has been confirmed (Korean Patent No. 0814092).
- HDAC histone deacetylase
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula 1 (alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate), a compound of formula 2 (alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate) or a combination thereof.
- R 1 is C 1-3 alkyl unsubstituted or substituted with one or more substituents selected from the group consisting of halophenyl, C 1-3 alkoxy, C 1-3 alkoxy C 1-3 alkyl, cyclohexanyl, furanyl, thiophenyl, imidazole, imidazolidyl C 1-3 alkyl, C 1-3 alkylamino, di-C 1-3 alkylamino, hydroxyphenyl, tetrahydrofuranyl, cyclohexyl, cyclohexenyl, oxopyrrolidinyl, C 1-3 alkoxyphenyl, di-C 1-3 alkylaminophenyl, C 1-3 alkylpyrrolidinyl and trifluoromethoxyphenyl; pyrrolidine unsubstituted or substituted with C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-3 alkyl, benzyl, C
- R 1 may be N,N-dimethylpropylamine.
- the present invention may provide an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide compound containing phosphate or tartrate, such as a compound of formula 1 or a compound of formula 2.
- alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide derivatives may be selected from the group consisting of the following compounds:
- a method for preparing a pharmaceutical composition comprising a compound of formula 1, a compound of formula 2, or a combination thereof, comprising:
- the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide or a derivative thereof may be in the form of a solid, gel or solution wherein the form of solution may refer to a state completely dissolved in an organic solvent or a suspension state.
- the organic solvent may comprise one or more selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile and ethyl acetate.
- it may comprise one or more selected from the group consisting of methanol, ethanol, propanol, tetrahydrofuran, chloroform, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO), which have relatively high solubility.
- the method may further comprise additionally adding a solvent having a lower solubility than the organic solvent of step 1).
- the solvent having a lower solubility than the organic solvent of step 1) may comprise one or more selected from the group consisting of alcohols including methanol, ethanol and propanol, tetrahydrofuran, acetonitrile and acetone.
- the precipitation that is, the formation of a salt is observed, and if necessary, a solvent with a lower solubility than the added organic solvent may be additionally added to observe the precipitation.
- the addition of the solvent having a lower solubility may be repeated 2 to 5 times, for example, 2 times to obtain a salt.
- the pharmaceutical composition of the present invention may be provided in the form of a tablet, granule, powder, capsule, dry syrup or injection. Specifically, it may be provided in any convenient form, such as in the form of tablets, pellets, granules, capsules, suspensions, emulsions or powders, which are suitable for reconstitution with water or other suitable liquid medium. In addition, it may be provided in the form of oral administration or injection.
- the pharmaceutical composition for oral administration may comprise at least one diluent selected from the group consisting of microcrystalline cellulose, mannitol, lactose and lactose, at least one lubricant selected from the group consisting of talc, magnesium stearate, sodium stearyl fumarate and glyceryl behenate, and at least one binder selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose.
- the coating layer may be included in an amount of 1 to 10% by weight based on 100% by weight of a tablet or capsule.
- the coating layer may include a water-soluble coating base material, and a commonly used coating base material may be used.
- it includes a coating base material including polyvinyl alcohol derivatives, methacrylic acid derivatives and polyacrylic acid derivatives, and for example, one or two or more selected from the group consisting of Opadry®, Kollicoat®, and hydroxypropyl methylcellulose (IPMC) may be used, for example polyvinyl alcohol containing Opadry® having a relatively excellent effect of blocking moisture and light may be used.
- a coating base material including polyvinyl alcohol derivatives, methacrylic acid derivatives and polyacrylic acid derivatives, and for example, one or two or more selected from the group consisting of Opadry®, Kollicoat®, and hydroxypropyl methylcellulose (IPMC) may be used, for example polyvinyl alcohol containing Opadry® having a relatively excellent effect of blocking moisture and light may be used.
- a granule composition for oral administration it is preferable not to use purified water as a binding solvent in consideration of the property of unstable moisture stability.
- Ethanol may be used that can be easily removed during the manufacturing process.
- Magnesium stearate which is a lubricant used in a conventional composition for oral administration, may not be suitable for mixing with the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide according to the present invention, so alternatives can be used.
- a pharmaceutical excipient having excellent compatibility with the compound can be added.
- the injection composition can be provided in a liquid form because the alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide component is a water-soluble material that is well soluble in water.
- solubilizing agents and other additives generally used to improve solubility of poorly soluble substances are not essential. It is preferable to use a minimum amount of additive as it may have unstable compatibility with the additives. More specifically, it can be prepared by dissolving in nitrogen-purged water for injection and then lyophilizing.
- the method may further comprise sterilizing.
- the sterilization method may include dry heat sterilization, pressurized or reduced pressure sterilization, filter sterilization, gas sterilization, radiation sterilization, and the like.
- a nitrocellulose membrane filter may be used, for example, and the filter having 0.45 ⁇ m or 0.2 ⁇ m pore size may be used.
- the method may further comprise sterilizing by a high-temperature decompression sterilization method or aseptic filtration method.
- a tablet composition having convenience of dosing and easy of manufacture, a tablet composition was prepared using alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate and additives having established stability in the compositions as shown in Table 1, based on the results of compatibility studies.
- a tablet composition was prepared by a granulation method using ethanol as a binding solvent, instead of a direct compression method.
- ethanol as a binding solvent
- the ratio of the excipient added was increased, thereby minimizing the influence of appearance of the main component.
- the mold release is expressed as good and poor.
- the sticking is expressed as ⁇ : non-sticking
- X sticking and ⁇ : good.
- the capping is expressed as ⁇ : no capping and X: occurrence of capping.
- Example 1 Example 2
- Example 3 Example 4 Sticking ⁇ ⁇ ⁇ ⁇ Mold release Poor Poor Poor Poor Capping X X X X
- tablets were manufactured by increasing the amount of excipients and decreasing the portion of the main ingredients as shown in Table 3.
- Table 4 shows the results of tableting evaluation.
- Example 5 Example 6
- Example 7 Example 8 1 Granulation CG200745PPA 125 125 125 125 2 Mannitol 220 250 250 280 3 Microcrystalline 200 220 220 220 cellulose 4 Silicon dioxide 5 5 5 5 7 Hydroxypropyl 30 30 30 30 cellulose 8 Post mixing Glyceryl behenate 30 30 50 9 Talc 10 10 10 10 Total weight 620 670 690 720
- Example 5 Example 6
- Example 7 Example 8 Sticking ⁇ ⁇ X X Mold release Poor Poor Good Good Capping X X X X
- CG200745PPA can be applied as an anticancer agent.
- Most of the subjects to be administered are patients undergoing chemotherapy. Therefore, if increasing in tablet size, it is not only very difficult to take, but also there is a fear of rejection in taking tablets. Accordingly, in the present invention, it was intended to improve it.
- a capsule formulation composition was prepared that has less physical influence on the manufacture and a simple process such as a tableting process. As shown in the composition of Table 5, for convenience of dosing, the minimum amount of excipients that can be manufactured was used, and for simplification of the process, the direct mixing was used.
- Table 6 General Chapters; 1174, USP
- EMBO CAPS hard capsule, manufactured by Suheung was used for capsule #0 and capsule #1.
- Example 10 1 Direct mixing CG200745PPA 125 125 2 Mannitol 80 90 3 Microcrystalline 70 80 cellulose 6 Magnesium 5 10 aluminometasilicate 9 talc 10 10 10 Sodium stearyl 5 10 fumarate Total weight 295 325
- Example 12 1 Granulation CG200745PPA 125 125 2 Mannitol 75 60 3 Microcrystalline 70 60 cellulose 6 Hydroxypropyl 10 8 cellulose 9 Talc 10 7 Total weight 290 260
- the capsules filled with granules showed good flowability and little mass deviation.
- a total weight of 290 mg was considered to be problematic when filling into Capsule #1 due to the large volume characteristics of the mixture. Accordingly, a composition with a total weight of mixture of 260 mg was selected.
- Example 8 In accordance with Korean Pharmacopoeia dissolution test method 2 (paddle method, apparatus 2), the formulation of Example 8 was subjected to an in vitro dissolution test. The dissolution tests were carried out in all 4 solutions, and the results are shown in FIG. 1 and Table 10.
- Example 12 In the same manner as in Experimental Example 1, in accordance with Korean Pharmacopoeia dissolution test method 2 (paddle method, apparatus 2), the formulation of Example 12 was subjected to an in vitro dissolution test. The dissolution tests were carried out in all 4 solutions, and the results are shown in FIG. 2 and Table 11.
- Example 12 In order to evaluate the amount of change in the related substances of Example 12, the composition of Example 12 was placed in an accelerated condition chamber (45° C. ⁇ 2, 75% ⁇ 5), and the amount of related substance produced was measured for 6 months. For the measurement of the amount of related substances produced, the composition of Example 12 was pretreated and then tested according to the liquid chromatography method of the general test method of the Korean Pharmacopoeia to determine peak areas of the produced related substances (individual related substance 0.2% or less, total related substances 1.0%, measuring equipment: HPLC LC-2030C_Shimadzu). The results are shown in Table 12 and FIG. 3 . In Table 12, the amount of related substances produced is expressed in %. In addition, FIG. 3 is a result of measuring the related substance at 28 minutes under the accelerated condition, and the reference value is 0.2%.
- an alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide compound was used in Comparative Example 1, an alkyl carbamoyl naphthalenyloxy octenoyl hydroxyamide tartrate was used in Example 13 and alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide phosphate was used in Example 14.
- alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide As alkylcarbamoyl naphthalenyloxy octenoyl hydroxyamide, (E)-N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide compound was used. Evaluation of stability was conducted by observing the change with storage time under room temperature (20-25° C., 50% or less), long-term (25 ⁇ 2° C. and 60 ⁇ 5% RH), accelerated (40 ⁇ 2° C. and 75 ⁇ 5% RH) and severe (60 ⁇ 2° C.) conditions.
- each compound was stored in an open state according to the conditions shown in Table 13 below, and then the change in appearance was observed.
- each compound was stored in an open state or in a polyethylene bottle packaging (silica gel added) to measure the change in content.
- sica gel added sica gel added
- compounds of Comparative Examples and Examples were pretreated and then the solutions were tested according to the liquid chromatography method of the general test methods of the Korean Pharmacopoeia to determine the peak area of CG200745 (measurement equipment: HPLC LC-2030C_Shimadzu).
- the content standard is to contain CG200745 in an amount corresponding to 95.0-105.5% of the indicated amount according to the standards and test methods of the present applicant.
- Example 13 the content was maintained at a certain level under the room temperature condition, and in the case of Example 14, the content was kept constant regardless of packaging conditions, heating, and humidity.
- each compound was stored in an open state at room temperature for 3 days, and then the amount of related substances produced was measured in the same manner as in Experimental Example 3 and the results are shown in FIG. 5 .
- the amount of related substances was increased by about 10% in Comparative Example 1, while the amount was increased by 0.05% in Example 13 and the amount was increased by 0.02% in Example 14, which were relatively insignificant.
- FIGS. 6 and 7 changes in the amount of related substances produced according to temperature and storage period are shown in FIGS. 6 and 7 for the compounds according to Examples 13 and 14.
- the amount of related substances produced in Example 13 was maintained within a certain range at a relatively low temperature.
- the amount of related substances produced in Example 14 was kept constant within a certain range of about 0.22% regardless of the storage temperature and period.
- CG200745PPA is an anticancer drug that can be administered to cancer patients for the purpose of cancer treatment
- various routes of administration should be considered according to the patient's condition.
- the route that can be administered to a subject having difficulties in oral administration includes intravenous or intramuscular injection.
- intravenous or intramuscular injection there are injections in a liquid form or a lyophilized form that is diluted immediately before use.
- a photograph of the prepared composition is shown in FIG. 8 .
- the CG200745PPA compound according to the present invention can improve the dissolution rate while maintaining properties such as medicinal efficacy and effective amount.
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KR1020180129576A KR102678356B1 (ko) | 2018-10-29 | 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 인산염, 타르타르산염 또는 이들의 조합을 포함하는 약제학적 조성물 및 그 제조방법 | |
PCT/KR2019/014234 WO2020091326A1 (ko) | 2018-10-29 | 2019-10-28 | 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 인산염, 타르타르산염 또는 이들의 조합을 포함하는 약제학적 조성물 및 그 제조방법 |
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WO2007052938A1 (en) * | 2005-11-01 | 2007-05-10 | Korea Research Institute Of Chemical Technology | Alkylcarbamoyl naphthalenyloxy- octenoylhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof |
WO2008054154A1 (en) * | 2006-11-03 | 2008-05-08 | Korea Research Institute Of Chemical Technology | Naphthalenyloxypropenyl derivatives having inhibitory activity against histone deacetylase and pharmaceutical composition comprising the same |
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FR1212723A (fr) * | 1958-01-09 | 1960-03-25 | Rhone Poulenc Sa | Nouveaux dérivés de la phénothiazine à chaîne carbamoylpipérazine et leur préparation |
EP1686115A1 (de) * | 2005-01-26 | 2006-08-02 | Novartis AG | Organische Säureadditionssalze von Valnemulin |
KR100711944B1 (ko) * | 2005-11-01 | 2007-05-02 | 한국화학연구원 | 히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일나프탈렌일옥시프로페닐 하이드록시벤즈아마이드 유도체,이의 제조방법 및 이를 유효성분으로 하는 항암제용 약학조성물 |
KR100814092B1 (ko) | 2006-11-03 | 2008-03-14 | 한국화학연구원 | 히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체, 이의제조방법 및 이를 유효성분으로 하는 항암제용 약학조성물 |
KR100814100B1 (ko) * | 2006-11-03 | 2008-03-14 | 한국화학연구원 | 히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일나프탈렌일옥시프로페닐 하이드록시벤즈아마이드 유도체,이의 제조방법 및 이를 유효성분으로 하는 항암제용 약학조성물 |
KR101388596B1 (ko) * | 2008-12-11 | 2014-04-24 | 대한민국 | 잠복성 hiv 감염 세포에서 hiv-1 프로바이러스를 재활성화시키는 히스톤 디아세틸라제 억제제 |
KR101978364B1 (ko) * | 2017-06-15 | 2019-05-14 | 크리스탈지노믹스(주) | 알킬카바모일 나프탈렌일옥시 옥테노일 하이드록시아마이드 또는 그 유도체의 약학적으로 허용 가능한 염 및 그 제조방법 |
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AU2019369913A1 (en) | 2021-05-06 |
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CN112930177A (zh) | 2021-06-08 |
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